UKPID MONOGRAPH
DELTAMETHRIN
SA Cage MSc M Inst Inf Sci
SM Bradberry BSc MB MRCP
S Meacham BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
DELTAMETHRIN
Toxbase summary
Type of product
Insecticide
Toxicity
Dermal and inhalational exposures are associated usually with no or
only mild adverse effects. Following substantial ingestion, patients
may develop coma, convulsions and severe muscle fasciculations and may
take several days, occasionally weeks, to recover.
Ingestion of deltamethrin 2 mg/kg body weight caused coma in a four
year old child. Recovery was uneventful (O'Malley, 1977).
Fatalities have occurred rarely after pyrethroid exposure, usually
following ingestion (He et al, 1989). Three fatalities have been
reported after deltamethrin exposure (He et al, 1989; Peter et al,
1996).
Features
Dermal exposure
- Tingling and pruritus with blotchy erythema on the face or
other exposed areas, exacerbated by sweating or touching.
Systemic toxicity may ensue following substantial exposure
(see below).
Ocular exposure
- Lacrimation and transient conjunctivitis may occur.
Inhalation
Brief exposure:
- Respiratory tract irritation with cough, mild dyspnoea,
sneezing and rhinorrhea.
Substantial and prolonged exposure:
- Systemic toxicity may ensue - see below.
Ingestion
- May cause nausea, vomiting and abdominal pain. Systemic
toxicity may ensue following substantial ingestion (see
below).
Systemic toxicity
- Systemic symptoms may develop after widespread dermal
exposure, prolonged inhalation or ingestion. Features
include headache, dizziness, anorexia and hypersalivation.
- Severe poisoning is uncommon. It usually follows substantial
ingestion and causes impaired consciousness, muscle
fasciculations, convulsions and, rarely, non-cardiogenic
pulmonary oedema.
Chronic exposure
- Long-term exposure is no more hazardous than short-term
exposure.
Management
Dermal
1. Remove soiled clothing and wash contaminated skin with soap and
water.
2. Institute symptomatic and supportive measures as required.
3. Topical vitamin E (tocopherol acetate) has been shown to reduce
skin irritation if applied soon after exposure (Flannigan et al,
1985), but it is not available as a pharmaceutical product in the
UK.
4. Symptoms usually resolve within 24 hours without specific
treatment.
Ocular
1. Irrigate with lukewarm water or 0.9 per cent saline for at least
ten minutes.
2. A topical anaesthetic may be required for pain relief or to
overcome blepharospasm.
3. Ensure no particles remain in the conjunctival recesses.
4. Use fluorescein stain if corneal damage is suspected.
5. If symptoms do not resolve following decontamination or if a
significant abnormality is detected during examination, seek an
ophthalmological opinion.
Inhalation
1. Remove to fresh air.
2. Institute symptomatic and supportive measures as required.
Ingestion
1. Do not undertake gastric lavage because solvents are present in
some formulations and lavage may increase risk of aspiration
pneumonia.
2. Institute symptomatic and supportive measures as required.
3. Atropine may be of value if hypersalivation is troublesome,
0.6-1.2 mg for an adult, 0.02 mg/kg for a child.
4. Mechanical ventilation should be instituted if non-cardiogenic
pulmonary oedema develops.
5. Isolated brief convulsions do not require treatment but
intravenous diazepam should be given if seizures are prolonged or
recur frequently. Rarely, it may be necessary to give intravenous
phenytoin or to paralyze and ventilate the patient.
References
Box SA, Lee MR.
A systemic reaction following exposure to a pyrethroid insecticide.
Hum Exp Toxicol 1996; 15: 389-90.
Flannigan SA, Tucker SB, Key MM, Ross CE, Fairchild EJ, Grimes BA,
Harrist RB.
Synthetic pyrethroid insecticides: a dermatological evaluation.
Br J Ind Med 1985; 42: 363-72.
He F, Wang S, Liu L, Chen S, Zhang Z, Sun J.
Clinical manifestations and diagnosis of acute pyrethroid poisoning.
Arch Toxicol 1989; 63: 54-8.
Lessenger JE.
Five office workers inadvertently exposed to cypermethrin.
J Toxicol Environ Health 1992; 35: 261-7.
O'Malley M.
Clinical evaluation of pesticide exposure and poisonings.
Lancet 1997; 349: 1161-6.
Peter JV, John G, Cherian AM.
Pyrethroid poisoning.
J Assoc Physicians India 1996; 44: 343-344.
Substance name
Deltamethrin
Origin of substance
Deltamethrin was first synthesized in 1974 and is marketed as a
single isomer [1R, cis; alpha S].
Synonyms/Proprietary names
Butox
Crackdown
Decamethrin
Decis
Deleet
Deltagran
Kordon
K-Othrin
Landgold deltaland
OMS 1988
Sadethrin
Standon deltamethrin
Thripstick (Pesticides 1997, 1997; RTECS,
1997; The UK Pesticide Guide, 1997)
Chemical group
Type II synthetic pyrethroid
Reference numbers
CAS 52918-63-5 (Pesticide Manual, 1997)
RTECS GZ1233000 (RTECS, 1997)
UN NIF
HAZCHEM CODE NIF
Physicochemical properties
Chemical structure
IUPAC name: (S)-alpha-cyano-3-phenoxybenzyl
(1 R)-cis-3-(2,2-dibromovinyl)-2,2-dimethyl-
cyclopropanecarboxylate
C22H19Br2NO3 (Pesticide Manual, 1997)
Molecular weight
505.2 (Pesticide Manual, 1997)
Physical state at room temperature
Solid (crystals) (Pesticide Manual, 1997)
Colour
Colourless (Pesticide Manual, 1997)
Odour
Odourless (HSDB, 1997)
Viscosity
NIF
pH
NIF
Solubility
Low solubility in water: < 2 x 10-7 g/L at 25°C
Acetone 500 g/L at 20°C
Benzene 450 g/L at 20°C
Cyclohexanone 750 g/L at 20°C
Dichloromethane 700 g/L at 20°C
Dimethyl sulphoxide 450 g/L at 20°C
Ethanol 15 g/L at 20°C
Isopropanol 6 g/L at 20°C
Xylene 250 g/L at 20°C (Pesticide Manual, 1997)
Autoignition temperature
NIF
Chemical interactions
NIF
Major products of combustion
Combustion and/or pyrolysis of deltamethrin can lead potentially
to the production of compounds such as formaldehyde, acrolein,
hydrogen cyanide and hydrogen bromide
(Hartzell, 1996).
Explosive limits
NIF
Flammability
Burns with difficulty. (HSDB, 1997)
Boiling point
NIF
Density
0.55 at 25°C (Pesticide Manual, 1997)
Vapour pressure
1.24 x 10 -8 Pa (25°C saturation method)
(Pesticide Manual, 1997)
Relative vapour density
NIF
Flash point
NIF
Reactivity
NIF
Uses
Deltamethrin is a potent insecticide effective by contact and
ingestion against a wide range of pests in cereals, cotton, fruit
and vegetables. It is used against indoor crawling and flying
insects and pests in stored grain and timber. Deltamethrin is
also used as an animal ectoparasiticide (Pesticide Manual, 1997).
Hazard/risk classification
NIF
INTRODUCTION
Pyrethrins were developed as pesticides from extracts of dried and
powdered flower heads of Chrysanthemum cinerariaefolium. The active
principles of these (see Fig. 1) are esters of chrysanthemumic acid
(R1 = CH3) or pyrethric acid (R1 = CH3O2C) (both cyclopropane
(three membered ring) carboxylic acids), with one of three
cyclopentanone alcohols (cinerolone, R2 = CH3; jasomolone, R2 =
CH2CH3; or pyrethrolone, R2 = CHCH2), giving six possible
structures. These natural pyrethrins have the disadvantage that they
are rapidly decomposed by light.
Once the basic structure of the pyrethrins had been discovered,
synthetic analogues, pyrethroids, were developed and tested. Initially
esters were produced using the same cyclopropane carboxylic acids,
with variations in the alcohol portion of the compounds.
The first commercial synthetic pyrethroid, allethrin, was produced in
1949, followed in the 1960s by others including dimethrin,
tetramethrin and resmethrin. 3-Phenoxybenzyl esters were also found to
be active as pesticides (e.g phenothrin, permethrin). Synthetic
pyrethroids with the basic cyclopropane carboxylic ester structure
(and no cyano group substitution) are known as type I pyrethroids. In
animal studies type I pyrethroids have been shown generally to produce
a typical toxic syndrome (see below).
The insecticidal activity of synthetic pyrethroids was enhanced
further by the addition of a cyano group at the benzylic carbon atom
to give alpha-cyano (type II) pyrethroids such as deltamethrin. In
animal studies type II pyrethroids have been shown generally to
produce a typical toxic syndrome (see below).
Despite the lack of the cyclopropane ring, similar insecticidal
activity was found in a group of phenylacetic 3-phenoxybenzyl esters.
This led to the development of fenvalerate, an
alpha-cyano-3-phenoxy-benzyl ester, and other related compounds such
as fluvalinate. These all contain the alpha-cyano group and hence are
type II pyrethroids.
Animal studies suggest that the two structural types of pyrethroids
give rise generally to distinct patterns of systemic toxic effects.
Type I pyrethroids produce in animals the so-called "T (tremor)
syndrome", characterized by tremors, prostration and altered "startle"
reflexes. Type II (alpha-cyano) pyrethroids produce the so-called "CS
(choreoathetosis/salivation) syndrome" with ataxia, convulsions,
hyperactivity, choreoathetosis and profuse salivation being observed
in experimental studies.
These observations are consistent with some differences in the
mechanisms of toxicity between type I and type II pyrethroids (see
below) but the division of reactions by chemical structure is not
exclusive. Some compounds produce a combination of the two syndromes,
and different stereoisomeric forms can produce different syndromes
(Dorman and Beasley, 1991). The classification into "T" and "CS"
syndromes is not used clinically.
All pyrethroids have at least four stereoisomers, with different
orientation of the substituents on the cyclopropane ring (or the
equivalent part of the phenylacetate) though deltamethrin is marketed
as a single isomer. The isomers have different biological activities,
as discussed below (see Mechanisms of toxicity). Different isomers may
have separate common names, reflecting their commercial importance
(Aldridge et al, 1978).
Further details are given in the pyrethroid generic monograph.
EPIDEMIOLOGY
In 1989-1990, world-wide annual production of pyrethroids was at least
2000 tonnes (IPCS, 1989a; IPCS, 1989b; IPCS, 1989c; IPCS, 1990a; IPCS,
1990b; IPCS, 1990c; IPCS, 1990d, IPCS, 1990e; IPCS, 1990f) including
some 250 tonnes of deltamethrin (IPCS, 1990d).
In spite of their long history of use, there are relatively few
reports of pyrethroid, and specifically deltamethrin, toxicity and
fewer than ten deaths have been reported from ingestion or
occupational (primarily dermal/inhalational) exposure, though three
deaths from deltamethrin poisoning have been reported (He et al, 1989;
Peter et al, 1996).
MECHANISMS OF TOXICITY
In neuronal cells the generation of an action potential by membrane
depolarization involves the opening of cell membrane sodium channels
and a rapid increase in sodium influx. The closure of sodium channels
begins the process of action potential inactivation. Delayed sodium
channel closure thus increases cell membrane excitability.
Pyrethroids modify the gating characteristics of voltage-sensitive
sodium channels in mammalian and invertebrate neuronal membranes
(Eells et al, 1992; Narahashi, 1989) to delay their closure. They are
dissolved in the lipid phase of the membrane (Narahashi, 1996) and
bind to a receptor site on the alpha sub-unit of the sodium channel
(Trainer et al, 1997). This binding is to a different site from local
anaesthetics, batrachotoxin, grayanotoxin, and tetrodotoxin
(Narahashi, 1996).
The interaction of pyrethroids with sodium channels is highly
stereospecific (Soderlund and Bloomquist, 1989), with the 1R and 1S
cis isomers binding competitively to one site and the 1R and 1S
trans isomers binding non-competitively to another. The 1S forms do
not modify channel function but do block the effect of the 1R isomers
(Ray, 1991).
The prolonged opening of sodium channels by the neurotoxic isomers of
pyrethroids produces a protracted sodium influx which is referred to
as a sodium "tail current" (Miyamoto et al, 1995; Soderlund and
Bloomquist, 1989; Vijverberg and van den Bercken, 1982). This lowers
the threshold of sensory nerve fibres for the activation of further
action potentials, leading to repetitive firing of sensory nerve
endings (Vijverberg and van den Bercken, 1990) which may progress to
hyperexcitation of the entire nervous system (Narahashi et al, 1995).
At high pyrethroid concentrations, the sodium "tail current" may be
sufficiently great to depolarize the nerve membrane completely,
generating more open sodium channels (Eells et al, 1992) and
eventually causing conduction block.
Only low pyrethroid concentrations are necessary to modify sensory
neurone function. For example, when tetramethrin was added to a
preparation of rat cerebellar Purkinje neurons, only about 0.6-1 per
cent of sodium channels needed to be modified to produce:
(i) Repetitive discharges in nerve fibres and nerve terminals;
(ii) An increase in discharges from sensory neurons (due to membrane
depolarization); and
(iii) Severe disturbances of synaptic transmission (Narahashi, 1989;
Narahashi et al, 1995; Song and Narahashi, 1996).
These effects on sodium channels are common to all pyrethroids
although specific effects of type II pyrethroids such as deltamethrin
have been clarified in experimental studies. These show that type II
compounds:
(i) Cause depolarization of myelinated nerve membranes without
repetitive discharges (Dorman and Beasley, 1991; Vijverberg and
van den Bercken, 1982);
(ii) Are associated with a decrease in action potential amplitude
(Dorman and Beasley, 1991);
(iii) Stabilize a variety of sodium channel states by reducing
transition rates between them (Dorman and Beasley, 1991; Eells
et al, 1992; Narahashi, 1989), causing a greatly prolonged open
time (Vijverberg and van den Bercken, 1982), and producing
stimulus-dependent nerve depolarization and block (Soderlund
and Bloomquist, 1989);
(iv) May act post-synaptically by interacting with nicotinic
acetylcholine and GABA receptors (Dorman and Beasley, 1991;
Eells et al, 1992);
(v) Produce effects on cultured neurons that are largely
irreversible after washing cells with a pyrethroid-free
solution (Song et al, 1996).
In addition, type II pyrethroids, such as deltamethrin, enhance
noradrenaline (norepinephrine) release (Clark and Brooks, 1989).
Oral deltamethrin increases monoamine oxidase activity selectively in
different parts of rat brains, and produces morphological changes in
Purkinje neurons in the cerebellum (Husain et al, 1996).
In human investigations, maximal conduction velocity in sensory nerve
fibres of the sural nerve showed some increase in subjects exposed to
pyrethroids, but there were no abnormal neurological signs, and other
electrophysiological studies were normal in the arms and legs (Le
Quesne et al, 1980). He et al (1991) assessed nerve excitability using
an electromyograph and pairs of stimuli at variable intervals. They
showed a prolongation of the "supernormal period" in the median nerve
in individuals who had been exposed to pyrethroids occupationally for
three days. The "supernormal period" was even more prolonged two days
after cessation of exposure. (Note: the "supernormal period" is the
period for which the action potential induced by a second stimulus is
greater than the action potential produced by an initial stimulus).
Pyrethroids are some 2250 times more toxic to insects than mammals.
This can be explained in terms of differences in their potency as
neuronal toxins and differences in rates of detoxification between
invertebrates and vertebrates (Narahashi, 1996; Narahashi et al, 1995;
Song and Narahashi, 1996).
The sensitivity of invertebrate neuronal sodium channels to
pyrethroids is ten times greater than in mammals (Song and Narahashi,
1996). Furthermore, invertebrates typically have body temperatures
some 10°C lower than mammals and in vitro studies show tetramethrin
to be more potent at evoking repetitive neuronal discharges at lower
temperatures (Song and Narahashi, 1996). In these experiments it was
noted that the recovery of sodium channels from tetramethrin
intoxication after washing was some five times faster in mammals than
invertebrates. In addition pyrethroid hepatic metabolism
(detoxification) is faster in mammals. Finally small insect size
increases the likelihood of end-organ (neuronal) toxicity prior to
detoxification (Song and Narahashi, 1996).
TOXICOKINETICS
In addition to the important differences between invertebrates and
vertebrates outlined above, the low toxicity of pyrethroid
insecticides in mammals is due to poor dermal absorption (the main
route of exposure) and metabolism to non-toxic metabolites (Bradbury
and Coats, 1989).
Absorption
Dermal
Based on excretion studies involving other pyrethroids (Nassif, et al,
1980; Chester et al, 1987; Eadsforth et al, 1988; IPCS, 1989c; Woollen
et al, 1991; Chester, 1992; Woollen et al, 1992; ) dermal absorption
of deltamethrin is likely to be low (less than 1.5 per cent).
When protective clothing was used the concentrations of deltamethrin
and metabolites in urine at the end of a working day were at the limit
of detection (IPCS, 1990d).
Oral
Between 19 and 57 per cent of orally administered cypermethrin
(another type II pyrethroid) was absorbed in human studies (Woollen et
al, 1991; Woollen et al, 1992) though there are no human data specific
to deltamethrin.
Metabolism
Pyrethroids are hydrolyzed rapidly in the liver to their inactive acid
and alcohol components (Hutson, 1979; Ray, 1991), probably by
microsomal carboxylesterase (Hutson, 1979). Further degradation and
hydroxylation of the alcohol at the 4' position then occurs, and
oxidation produces a wide range of metabolites (Hutson, 1979; Leahey,
1985).
There is some stereospecificity in metabolism, with trans-isomers
being hydrolyzed more rapidly than the cis-isomers, for which
oxidation is the more important metabolic pathway (Soderlund and
Casida, 1977). Although the alpha-cyano group reduces the
susceptibility of the molecule to hydrolytic and oxidative metabolism
(Hutson, 1979; Soderlund and Casida, 1977), the cyano group is
converted to the corresponding aldehyde (with release of the cyanide
ion), followed by oxidation to the carboxylic acid, sufficiently
rapidly for efficient excretion by mammals (Leahey, 1985). Other
differences in the chemical structure of pyrethroids have less effect
on rates of metabolism (Soderlund and Casida, 1977).
The pattern of metabolites varies between oral and dermal dosing in
humans (Wilkes et al, 1993). For example, following dermal dosing with
cypermethrin (another type II pyrethroid) the ratio of trans/cis
cyclopropane acids excreted was approximately 1:1, compared to 2:1
after oral administration. Such measurements might be useful in
determining the route of exposure (Woollen, 1993; Woollen et al, 1991;
Woollen et al, 1992).
Animal studies have shown that pyrethroid hydrolysis is inhibited by
dialkylphosphorylating agents such as organophosphorus insecticides
(Abou-Donia et al, 1996; He et al, 1990; Hutson, 1979), and urinary
excretion of unchanged pyrethroid was higher in sprayers using a
methamidophos/ deltamethrin or methamidophos/fenvalerate mixture than
from those using the pyrethroid alone (Zhang et al, 1991).
Experiments with chickens (Abou-Donia et al, 1996) showed that
pyrethroid (permethrin) toxicity was also enhanced by pyridostigmine
bromide and by the insect repellent N,N-diethyl-m-toluamide (DEET).
The authors hypothesized that competition for hepatic and plasma
esterases by these compounds led to decreased pyrethroid breakdown and
increased transport of the pyrethroid to neural tissues.
Elimination
Deltamethrin is excreted mainly as metabolites in urine but a
proportion is excreted unchanged in faeces. An overview of human
pyrethroid elimination data is included in the generic pyrethroid
monograph.
After occupational exposure, deltamethrin and metabolites were
detectable in urine for up to 12 hours (Zhang et al, 1991).
Deltamethrin and metabolites were detectable in the urine of workers
spraying the pyrethroid early on the first day of spraying, and
persisted for up to two days after spraying had ceased (He et al,
1991).
CLINICAL FEATURES: ACUTE EXPOSURE
Occupationally, the main route of pyrethroid absorption is through the
skin; inhalation is much less important (Adamis et al, 1985; Chen et
al, 1991; Zhang et al, 1991). Inhalation is more likely when
pyrethroids are used in confined spaces (Llewellyn et al, 1996). The
use of protective clothing can reduce dermal exposure (Chester et al,
1987). The physical formulation also affects exposure, with inhalation
being more important for dust and powder formulations, and dermal
exposure more important for liquids (Llewellyn et al, 1996).
Dermal exposure
This is the most common route of pyrethroid exposure. Adverse effects
manifest primarily as peripheral neurotoxicity with reversible
hyperactivity of sensory nerve fibres (paraesthesiae), though erythema
and pruritus are also described (see below).
Peripheral neurotoxicity
Paraesthesiae have been reported frequently after deltamethrin
exposure (Chen et al, 1991; He et al, 1988; He et al, 1989; IPCS,
1990d; Le Quesne et al, 1980; Wang et al, 1988; Zhang et al, 1991),
particularly after inappropriate handling. Paraesthesiae occur most
commonly on the face (He et al, 1991). It seems probable that
paraesthesiae are related to the repetitive firing of sensory nerve
endings in contaminated skin (Aldridge, 1990) and not to inflammation
as there is little effect on neurogenic vasodilatation (Flannigan and
Tucker, 1985b). The symptoms are exacerbated by sensory stimulation
(heat, sun, scratching) (Aldridge, 1990), sweating or application of
water and may prevent sleep (Tucker and Flannigan, 1983).
In two studies, paraesthesiae were reportedly more severe after
deltamethrin than after other pyrethroid exposure (Aldridge, 1990;
Flannigan and Tucker, 1985a).
Twenty-two of 44 farmers exposed to airborne deltamethrin 2.5 per cent
(by inhalation and skin contact) complained of "itching and burning
sensations" on their faces, but deltamethrin in the urine was below
0.2 µg/L, the limit of detection (Wang et al, 1988). Contamination of
face, hands and feet with large quantities of 2.5 per cent
deltamethrin resulted in severe pain and numbness in the extremities
with muscle tremor; these symptoms disappeared within seven days (Wang
et al, 1988). One drop of 2.5 per cent deltamethrin dripped into an
open foot wound caused local pain but no inflammation (He et al,
1989).
Paraesthesiae generally start 30 minutes to two hours after exposure
and peak after about six hours. Recovery is usually complete within 24
hours (Aldridge, 1990; He et al, 1989; Knox and Tucker, 1982; Knox et
al, 1984; Tucker and Flannigan, 1983).
Dermal toxicity
When used at recommended doses in the treatment of scabies and lice,
pyrethroids only rarely produce adverse effects. Pruritus is the
side-effect reported most frequently (Brandenburg et al, 1986;
DiNapoli et al, 1988), although this may also be caused by the skin
infestation being treated.
Skin irritation during occupational pyrethroid exposure may occur in
up to ten per cent of workers (Kolmodin-Hedman et al, 1982) and may be
influenced by the ratio of stereoisomers used in the pyrethroid
formulation, being more sever with a higher proportion of the trans
isomer. In addition to pruritus, erythema, burning and blisters have
been reported (Brandenburg et al, 1986; Kalter et al, 1987; IPCS,
1990b; Kolmodin-Hedman et al, 1995).
Dermatitis with blisters and miliary papules has been reported in
those occupationally exposed to deltamethrin (Wang et al, 1988; He et
al, 1989).
Ocular exposure
Symptoms of mild eye irritation have been reported following
occupational pyrethroid exposure (Kolmodin-Hedman et al, 1982; IPCS,
1990d; Lessenger, 1992) though there are no reports specific to
deltamethrin.
Inhalation
Inhalational pyrethroid exposure typically is occupational and
produces symptoms and signs of pulmonary tract irritation. The
frequency and severity of symptoms may vary with the ratio of
different stereoisomers in a formulation, being more prevalent with a
higher proportion of the trans isomer. Systemic effects may occur
following more substantial exposure (He et al, 1989) and are described
below.
Irritation of the respiratory tract was reported among workers
producing an aerosol of deltamethrin (IPCS, 1990d).
Ingestion
Pyrethroid ingestion typically gives rise to nausea, vomiting and
abdominal pain within minutes. In one series (He et al, 1989)
involving some 344 cases, vomiting was a prominent feature in 56.8 per
cent. The Chinese literature includes a case of erosive gastritis with
haematemesis following ingestion of 900 mL deltamethrin solution
(concentration not given) (Poisindex, 1996). In another case,
permethrin/pyrethrins accidentally sprayed directly into the mouth
resulted in a burning sensation which commenced several hours after
exposure, and only gradually improved over five months, with
persistent disordered taste sensation (Grant, 1993).
Substantial deltamethrin ingestion may give rise to neurological
features and other systemic effects as discussed below.
Systemic effects
Systemic effects generally have occurred after inappropriate
occupational handling of pyrethroids. This may involve using too
concentrated solutions, prolonged exposure, spraying against the wind
or using unprotected hands or mouth to unblock congested sprayers (He
et al, 1989). Most reported cases have involved dermal, inhalational
and sometimes also oral exposure to fenveralate, deltamethrin or
cypermethrin with systemic features occurring between four and 48
hours after spraying (He et al, 1989). Intentional ingestion may also
produce systemic effects (He et al, 1989; Peter et al, 1996). Most
patients recover over two to four days with only seven fatalities
among 573 cases in one review (He et al, 1989). Four of the seven
fatalities developed convulsions, one patient died from
non-cardiogenic pulmonary oedema, one from "atropine intoxication" and
one death followed exposure to a pyrethroid/organophosphorus pesticide
combination.
A further death has been reported recently in a patient who became
comatose within ten hours of 30 mL deltamethrin ingestion and died
from aspiration pneumonia complicated by renal failure (Peter et al,
1996).
Gastrointestinal toxicity
As discussed above gastrointestinal irritation is common following
pyrethroid ingestion. Vomiting was a prominent symptom also in 16 per
cent of occupational cases (He et al, 1989) in whom ingestion was
not suspected, but where exposure involved deltamethrin and other
pyrethroids. In this review, which included occupational exposures,
anorexia occurred in 45 per cent of 573 cases of acute pyrethroid
poisoning (He et al, 1989).
Neurotoxicity
He (1989) described dizziness in 60.6 per cent, headache in 44.5 per
cent, fatigue in 26 per cent, increased salivation in 20 per cent and
blurred vision in seven per cent of 573 cases of acute pyrethroid
poisoning (229 occupational and 344 accidental exposures).
Limb muscle fasciculations, coma and convulsions may complicate severe
acute pyrethroid poisoning, and have occurred as soon as 20 minutes
after ingestion (He et al, 1989). "Convulsions" was the stated cause
of death in four of seven fatalities among 573 cases of acute
pyrethroid poisoning (He et al, 1989) but further details were not
given.
An electromyelogram (EMG) in one case of acute pyrethroid poisoning
showed repetitive muscle discharges without denervation potentials (He
et al, 1989). Transient slow and sharp waves with high amplitude were
seen on electroencephalogram in a 23 year-old female following three
days "heavy dermal exposure" to deltamethrin. She did not have a
seizure but complained of headache, nausea, dizziness, anorexia and
fatigue with clinical evidence of muscle fasciculations (He et al,
1989). She recovered over several weeks with symptomatic and
supportive care.
O'Malley (1997) described a four year-old who was found unconscious
less than 20 minutes after ingesting approximately 2 mg/kg
deltamethrin (as a chalk containing 0.98 per cent pyrethroid). She
recovered uneventfully within a few hours.
A 21 year-old female developed headache and muscle fasciculations some
five hours after ingesting 30 mL 2.5 per cent deltamethrin with
suicidal intent (He et al, 1989). Eight hours later she developed
convulsions which persisted for two weeks and were treated with
diazepam and baclofen. An electromyelogram, electrocardiogram and
electroencephalogram were normal. She was discharged in good health 21
days after exposure.
A 25 year-old female sprayed cotton fields for three days using a
1:9000 dilution of 2.5 per cent deltamethrin:water, without a
protective mask and clothing such that her clothes became "heavily
soaked with deltamethrin" (He et al, 1989). She developed a burning,
tingling sensation in her cheeks in association with headache,
vomiting, limb-muscle fasciculations and convulsions (He et al, 1989).
The initial diagnosis was acute organophosphorus insecticide poisoning
but there was no improvement with oxime therapy. She recovered over
four weeks with symptomatic and supportive care.
A 30 year-old male was unresponsive on arrival a hospital some ten
hours after allegedly consuming 30 mL deltamethrin (Peter et al,
1996). He had radiological evidence of aspiration pneumonia and
biochemical evidence of renal failure. He was treated supportively but
developed convulsions and died within 48 hours.
Cardiovascular toxicity
Palpitation was reported in 13.1 per cent of 573 cases of acute
pyrethroid poisoning involving oral, inhalational and dermal exposure
(He et al, 1989). An electrocardiogram (ECG) showed ST and T wave
changes in eight of 71 patients. Other ECG abnormalities included
sinus tachycardia, ventricular ectopics and (rarely) sinus bradycardia
(He et al, 1989). All ECG changes resolved over 2-14 days.
Pulmonary toxicity
Chest tightness has been described following accidental or deliberate
ingestion of deltamethrin, fenvalerate or cypermethrin (He et al,
1989).
Non-cardiogenic pulmonary oedema has been reported rarely following
substantial pyrethroid ingestion, usually in association with severe
neurological complications and may contribute to a fatal outcome (He
et al, 1989).
Musculoskeletal toxicity
A case of acute polyarthralgia after skin exposure to flumethrin
(another type II pyrethroid) has been reported recently (Box and Lee,
1996).
Haemotoxicity
Among 235 cases of occupational or accidental acute pyrethroid
poisoning in whom a full blood count was performed, 15 per cent showed
a leucocytosis (He et al, 1989); this was probably a non-specific
response.
Nephrotoxicity
Urinalysis among 124 patients with acute pyrethroid poisoning
(involving oral, dermal and inhalational exposure to deltamethrin and
other pyrethroids) showed three patients with haematuria (He et al,
1989).
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
Few long-term adverse effects from pyrethroids have been reported
(IPCS, 1990d; Chen et al, 1991, He, 1994). There is no confirmed
evidence that repeated exposure to pyrethroids leads to permanent
damage to sensory nerve endings (Vijverberg and van den Bercken,
1990).
In plant workers dermally exposed to deltamethrin, slight desquamation
occurred (which could have been due to the hydrocarbon solvent). The
desquamation was restricted to the area contaminated with
deltamethrin, and was sometimes accompanied by pruritus (IPCS, 1990d).
One hundred and ninety-nine workers employed in a pyrethroid packaging
plant over four to five months on two occasions (winter and summer
sessions) were observed for cutaneous effects (He et al, 1988). Work
involved transferring pyrethroid emulsions (deltamethrin 2.5 per cent,
fenvalerate 20 per cent and (to a lesser extent) cypermethrin 10 per
cent) in xylene, from large containers to fill some 50,000 100 mL
bottles daily. Gloves (and gauze masks) were used in winter only with
no protective measures in summer. One hundred and forty of 199 (70 per
cent) workers complained of "abnormal facial sensation" with burning,
tingling, itching, tightness or numbness. Symptoms were more prevalent
(p<0.05) in summer, occurring in 92 per cent of summer workers (n=87)
compared to only 54 per cent of winter workers (n=112). Red miliary,
mildly pruritic papules were found in 14 per cent of all workers,
mainly on the face and chest and again were more prevalent (p<0.05)
in summer. This was probably due to increased sweating during summer
months (which tends to exacerbate cutaneous symptoms), but may also
have been contributed to by the absence of protective measures during
summer (He et al, 1988). The symptoms described in this study are
identical to those following acute pyrethroid exposure and did not
last more than 24 hours once subjects were away from the work
environment. This suggests there are no true chronic effects from
repeated pyrethroid exposure.
Inhalation
The 199 workers described above were exposed to estimated deltamethrin
ambient air concentrations of 0.005-0.012 mg/m3 and complained of
sneezing and increased nasal secretions but these symptoms were only
present at work, again suggesting no difference in effect between
chronic or acute pyrethroid exposure. Systemic symptoms of dizziness,
fatigue and nausea were mild and reported by only 14, nine and ten per
cent of workers respectively.
MANAGEMENT
Dermal exposure
Decontamination
Clothes contaminated with deltamethrin should be removed, and
contaminated skin washed with soap and water (He, 1994).
Specific measures
Topical alpha tocopherol (vitamin E) to treat paraesthesiae
As paraesthesiae usually resolve in 12-24 hours, specific treatment is
not generally administered or required. However, the topical
application of dl-alpha tocopherol acetate (vitamin E) has been
shown to reduce the severity of skin reactions to other pyrethroids
including fenvalerate (IPCS, 1990c; Tucker et al, 1984; Tucker et al,
1983), flucythrinate, permethrin and cypermethrin (Flannigan and
Tucker, 1985a). The reaction to cypermethrin was completely inhibited
by vitamin E (Flannigan et al, 1985). Vitamin E appears to be useful
both prophylactically and therapeutically (Flannigan and Tucker,
1985a). In a controlled human volunteer study, a commercial vitamin E
oil preparation produced 98 per cent inhibition of the cutaneous
symptoms from fenvalerate when applied immediately (Flannigan et al,
1985). At four hours the inhibition was only 50 per cent (Advisory
Committee on Pesticides, 1992). The mechanism of the effect of topical
vitamin E has not been clarified, although some in vitro studies
suggest vitamin E may block the pyrethroid-induced sodium "tail
current" in neuronal membranes (Song and Narahashi, 1995).
Vitamin E is not included in the British National Formulary but is
available from health food or alternative medicine sources.
Other agents to treat paraesthesiae
Various other topical therapies have been tested for treatment of
pyrethroid-induced paraesthesiae: in human trials mineral oil, corn
oil and "A&D ointment" (Tucker et al, 1984; Tucker et al, 1983) were
almost as effective as Vitamin E cream (but the oils may lead to
defatting of skin). Butylated hydroxyanisole and an industrial barrier
cream (Tucker et al, 1984) and topical indomethacin (Flannigan and
Tucker, 1984), were of little therapeutic benefit and in two studies
zinc oxide paste exacerbated paraesthesiae (Tucker et al, 1984; Tucker
et al, 1983) .
Ocular exposure
Irrigate the affected eye with lukewarm water or 0.9 per cent saline
for at least ten minutes. A topical anaesthetic may be required for
pain relief or to overcome blepharospasm. Ensure no particles remain
in the conjunctival recesses. Use fluorescein if corneal damage is
suspected. If symptoms do not resolve following decontamination or if
a significant abnormality is detected during examination, seek an
ophthalmological opinion.
Inhalation
Removal from exposure is the priority. Mild symptoms of rhinitis
respond to oral antihistamines. Other symptomatic and supportive
measures should be dictated by the patient's condition.
Ingestion
Gut decontamination
Gastric lavage should be avoided since solvents present in many
deltamethrin formulations may increase the risk of aspiration
pneumonia.
Systemic toxicity
Most patients exposed to pyrethroids require only simple supportive
care. Systemic toxicity is rare but in such patients the presence of
excess salivation, muscle fasciculations and pulmonary oedema may
present diagnostic difficulty since similar features are typical also
of severe organophosphorus pesticide poisoning. Measurement of the red
cell cholinesterase activity (which is reduced in acute
organophosphorus poisoning but not in pyrethroid intoxication) allows
clarification but may not be available rapidly.
Isolated brief convulsions do not require treatment but intravenous
diazepam 5-10 mg should be given if seizures are prolonged. Rarely it
may be necessary to give intravenous phenytoin, or to paralyze and
ventilate the patient. Diazepam is useful also in the treatment of
muscle fasciculations. The role of atropine is discussed below.
Several experimental studies have investigated the role of
pharmaceuticals in the management of the neurological complications of
severe pyrethroid poisoning. However, these should be interpreted with
caution, not only because they usually have involved high-dose
parenteral pyrethroid administration, but also because there is
considerable interspecies variation with regard to therapeutic
efficacy (Casida et al, 1983; Vijverberg and van den Bercken, 1990).
Atropine for hypersalivation and pulmonary oedema
In experimental studies atropine sulphate (25 mg/kg subcutaneously)
reduced hypersalivation produced by oral fenvalerate or cypermethrin
(each at a dose exceeding the LD50), but did not increase survival
(Hiromori et al, 1986).
Intravenous atropine (0.6-1.2 mg in an adult) may be useful to control
excess salivation but care should be taken to avoid excess
administration. In a review of pyrethroid poisoning cases reported
from China (He et al, 1989), 189 of 573 patients were treated with
atropine which led to an improvement in salivation and pulmonary
oedema in a few severe cases, but eight patients developed atropine
intoxication following intravenous administration of 12-75 mg. One
patient, probably misdiagnosed as having acute organophosphorus
insecticide poisoning, died of atropine intoxication after a total
dose of 510 mg, and one patient acutely intoxicated with a
fenvalerate/dimethoate mixture could not be revived despite a total
atropine dose of 170 mg.
Atropine and ethylcarbamate
In a French study a combination of intravenous atropine 3 mg/kg and
ethylcarbamate 1000 mg/kg effectively protected rodents against the
lethal effects of intravenous deltamethrin, increasing the LD50 by a
factor of 3.48 (Leclercq et al, 1986).
Diazepam and phenobarbital for convulsions
In mice (n=10) pre-treatment with intraperitoneal diazepam (1 mg/kg),
but not phenobarbital (10-30 mg/kg), significantly increased the time
to onset of convulsions caused by the intracerebroventricular
administration of deltamethrin (p< 0.005) and fenvalerate (p<0.05)
(Gammon et al, 1982). Under the same conditions diazepam was not
effective in preventing permethrin- or allethrin-induced seizures.
Propranolol and procainamide for tremor
Pre-treatment with intravenous propranolol or procainamide (each 15
µmol/kg) reduced the severity of tremor or writhing induced in rats by
the intravenous administration of deltamethrin (10 µmol/kg) (Bradbury
et al, 1983).
Ivermectin and pentobarbital for choreoathetosis
In rodents administered 2 mg/kg intravenous deltamethrin,
pre-treatment with 4 mg/kg intravenous ivermectin reduced
choreoathetosis from 3.9 to 3.2 (as graded on a scale of 1-4)
(p = 0.023), and reduced salivation by 72 per cent. Pentobarbital (15
mg/kg i.p.) reduced choreoathetosis produced by 1.5 mg/kg intravenous
deltamethrin from 3.0 to 1.3 (p = 0.004). An equi-sedative dose of
phenobarbital produced a non-significant fall to 2.4 (p = 0.11)
(Forshaw and Ray, 1997).
Mephenesin and methocarbamol
The skeletal muscle relaxant mephenesin 22 µmol/kg prevented all motor
symptoms induced in rats by the intravenous administration of
deltamethrin (10 µmol/kg) (n=4-20 in different treatment groups)
(Bradbury et al, 1983).
Mephenesin has a short half-life in vivo, but intraperitoneal
methocarbamol (a mephenesin derivative) (400 mg/kg intraperitoneally
followed by 200 mg/kg whenever tremor was observed) significantly
(p<0.01) reduced mortality in rats administered more than the oral
LD50 of fenvalerate, fenpropathrin, cypermethrin or permethrin (n=10
in each treatment group) (Hiromori et al, 1986).
There are insufficient data to advocate a clinical role for
methocarbamol in systemic pyrethroid toxicity.
Sodium-channel blockers (local anaesthetics)
In vitro studies suggest local anaesthetics may be useful as
antagonists of the effect of deltamethrin on sodium channels
(Oortgiesen et al, 1990). The relevance to human poisoning is not
known.
MEDICAL SURVEILLANCE
Avoiding dermal and inhalational exposure via adequate self-protection
and sensible use is the most important requirement to reduce adverse
effects from occupational use of deltamethrin.
OCCUPATIONAL DATA
Maximum exposure limit
International Standards Organization (ISO) limits for natural
pyrethrins are: long-term exposure limit (8 hour TWA reference period)
5 mg/m3; short-term exposure limit (15 min reference period) 10
mg/m3 (Health and Safety Executive, 1995).
OTHER TOXICOLOGICAL DATA
Endocrine toxicity
In vitro studies show that several pyrethroids interact
competitively with human skin fibroblast androgen receptors and with
sex hormone binding globulin (Eil and Nisula, 1990). A possible
anti-androgenic effect of pyrethroids in humans was suggested
following an outbreak of gynaecomastia in refugees exposed to
fenothrin, but there was insufficient evidence to confirm this (Eil
and Nisula, 1990).
Animal studies evaluating other endocrine effects of pyrethroids have
produced conflicting results (Akhtar et al, 1996; Kaul et al, 1996).
Immunotoxicity
Oral deltamethrin 5-10 mg/kg body weight daily for 28 days produced
thymus atrophy in rodents (Madsen et al, 1996) and a single
intraperitoneal dose of deltamethrin 6-50 mg/kg also caused a
reduction in thymus weight, which was dose- and time-dependant
(maximum effect two weeks after dosing) (Enan et al, 1996).
The significance of these immunological studies to man is not known.
Carcinogenicity
There is no evidence that deltamethrin is carcinogenic (IPCS, 1990d;
IARC, 1991).
Reprotoxicity
In a variety of animal studies, there was no evidence that
deltamethrin was teratogenic, embryotoxic or fetotoxic (IPCS, 1990d;
Reprotox, 1997).
Genotoxicity
Data regarding the potential genotoxicity of pyrethroids provide
conflicting results (Puig et al, 1989; Barrueco et al, 1992; Herrera
et al, 1992; Dolara et al, 1992; Barrueco et al, 1994; Surrallés et
al, 1995), though toxicity reviews of in vitro and in vivo data
for deltamethrin conclude that there is insufficient evidence for
deltamethrin to be considered genotoxic or mutagenic (IPCS, 1990d;
DOSE, 1997).
Tests with deltamethrin showed no genotoxicity with Salmonella
typhimurium TA98, TA100 or with Escherichia coli WP2 with or
without metabolic activation. Deltamethrin did not cause DNA damage in
Saccharomyces cerevisiae with or without metabolic activation (DOSE,
1997).
Deltamethrin induced chromosomal aberrations in root meristerm cells
of Allium cepa but did not induce gene mutation in Chinese hamster
V79 cells, with or without metabolic activation. No chromosomal
aberrations were observed in mouse bone marrow cells in vivo but
morphological sperm abnormalities were induced in mice (DOSE, 1997).
Fish toxicity
Deltamethrin is toxic to fish. It is more toxic at cooler
temperatures, and thus more toxic to cold than warm water fish, but
the toxicity of pyrethroids is little affected by pH or water hardness
(Mauck et al, 1976).
LC50 (96 hr) for mirror carp, rainbow trout, cichlid and pumpkinseed
sunfish range from 0.5 to 1.8 µg/L deltamethrin (DOSE, 1997).
EC Directive on Drinking Water Quality 80/778/EEC
Maximum admissible concentration (any pesticide) 0.1 µg/L (EC
Directive, 1980).
AUTHORS
SA Cage MSc M Inst Inf Sci
SM Bradberry BSc MB MRCP
S Meacham BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service (Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
UK
This monograph was produced by the staff of the Birmingham Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Date of last revision
28/1/98
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